The cellular transcription factor HIF (Hypoxia Inducible Factor) occupies a central position in oxygen homeostasis in a wide range of organisms and is a key regulator of responses to hypoxia. The genes regulated by HIF transcriptional activity can play critical roles in angiogenesis, erythropoiesis, hemoglobin F production, energy metabolism, inflammation, vasomotor function, apoptosis and cellular proliferation. HIF can also play a role in cancer, in which it is commonly upregulated, and in the physiological responses to ischemia and hypoxia.
The HIF transcriptional complex comprises an heterodimer (HIFαβ): HIF-β is a constitutive nuclear protein that dimerizes with oxygen-regulated HIF-α subunits. Oxygen regulation occurs through hydroxylation of the HIF-α subunits, which are then rapidly destroyed by the proteasome. In oxygenated cells, the von Hippel-Lindau tumor suppressor protein (pVHL protein) binds to hydroxylated HIF-subunits, thereby promoting their ubiquitin dependent proteolysis. This process is suppressed under hypoxic conditions, stabilizing HIF-α and promoting the transcription and activation of the HIFαβ dimer.
Hydroxylation of HIF-α subunits can occur on proline and asparagine residues and can be catalyzed by a family of 2-oxoglutarate dependent enzymes. This family includes the HIF prolyl hydroxylase isozymes (PHDs), which hydroxylate Pro 402 and Pro 564 of human HIF1α, as well as Factor Inhibiting HIF (FIH), which hydroxylates Asn 803 of human HIF1. Inhibition of FIH or the PHDs leads to HIF stabilization and further transcription and activation.
Inhibition of PHDs also leads to HIF stabilization and promoting transcriptional activation by the HIF complex, which may in turn provide a potential treatment for ischemia or anemia. There have been multiple patents that cover the chemical structure designs of the potential PHDs inhibitors, see, e.g., WO2004108681, WO2007070359 and WO2011006355.